Long assumed to be a mere “relay,” an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health revealed that the thalamus sustains the ability to distinguish categories and hold thoughts in mind.

By manipulating activity of thalamus neurons, scientists were able to control an animal’s ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say.

“If the brain works like an orchestra, our results suggest the thalamus may be its conductor,” explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH’s National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). “It helps ensembles play in-sync by boosting their functional connectivity.”

Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia, and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience.

The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers.

Two of the groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain’s thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems.

Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward.

Optogenetically suppressing neuronal activity in the thalamus blocked the mice’s ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals’ performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory.

What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons.

Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse’s ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay – and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain’s memory hub, the hippocampus.

Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. “Top-down” signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus were required to encode in PFC neurons the location of the reward – analogous to the correct door in the Halassa experiment.

“Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input,” noted Gordon. “Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.”

In their study, the Janelia team and Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held in the cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa.

“Our results show that cortex circuits alone can’t sustain the neural activity required to prepare for movement,” explained Gerfen. “It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit.”

NIH scientists try to crack the brain’s memory codes

Cracking the brain’s memory codes Scientists at NIH used electrical recordings to study how the human brain remembers.Courtesy of Zaghloul lab, NIH/NINDS.

In a pair of studies, scientists at the National Institutes of Health explored how the human brain stores and retrieves memories. One study suggests that the brain etches each memory into unique firing patterns of individual neurons. Meanwhile, the second study suggests that the brain replays memories faster than they are stored.

The studies were led by Kareem Zaghloul, M.D., Ph.D., a neurosurgeon-researcher at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Persons with drug resistant epilepsy in protocols studying surgical resection of their seizure focus at the NIH’s Clinical Center enrolled in this study. To help locate the source of the seizures, Dr. Zaghloul’s team surgically implanted a grid of electrodes into the patients’ brains and monitored electrical activity for several days.

“The primary goal of these recordings is to understand how to stop the seizures. However, it’s also a powerful opportunity to learn how the brain works,” said Dr. Zaghloul.

For both studies, the researchers monitored brain electrical activity while testing the patients’ memories. The patients were shown hundreds of pairs of words, like “pencil and bishop” or “orange and navy,” and later were shown one of the words and asked to remember its pair.

In one study, published in the Journal of Neuroscience, the patients correctly remembered 38 percent of the word pairs they were shown. Electrical recordings showed that the brain waves the patients experienced when they correctly stored and remembered a word pair often occurred in the temporal lobe and prefrontal cortex regions. Nevertheless, the researchers showed that the waves that appeared when recalling the words happened faster than the waves that were present when they initially stored them as memories.

In the second study, published in Current Biology, the researchers used a new type of grid, called a high density microelectrode array, to monitor the activity of dozens of individual neurons during the memory tests. The arrays were implanted into the middle temporal gyrus, a part of the brain thought to control word, face and distance recognition.

In this study, the patients correctly remembered 23 percent of the word pairs. When the researchers looked at the electrical recordings, they found that the pattern of neurons that fired when the patients correctly recalled a word pair appeared to be similar to the pattern of neurons that fired when they first learned the pair. Moreover, the results showed that the overall activity of the neurons was specific to each individual word pair and was quietest when the patients correctly remembered a pair, suggesting that the brain only uses a small proportion of neurons to represent each memory.

“These results support the idea that each memory is encoded by a unique firing pattern of individual neurons in the brain,” concluded Dr. Zaghloul.

Clock stars: Astrocytes keep time for brain, behavior

Until recently, work on biological clocks that dictate daily fluctuations in most body functions, including core body temperature and alertness, focused on neurons, those electrically excitable cells that are the divas of the central nervous system.

Asked to define the body’s master clock, biologists would say it is two small spheres — the suprachiasmatic nuclei, or SCN — in the brain that consist of 20,000 neurons. They likely wouldn’t even mention the 6,000 astroglia mixed in with the neurons, said Erik Herzog, a neuroscientist in Arts & Sciences at Washington University in St. Louis. In a March 23 advance online publication from Current Biology, Herzog and his collaborators show that the astroglia help to set the pace of the SCN to schedule a mouse’s day.

The astroglia, or astrocytes, were passed over in silence partly because they weren’t considered to be important. Often called “support cells,” they were supposed to be gap fillers or place holders. Their Latin name, after all, means “starry glue.”

Then two things happened. Scientists discovered that almost all the cells in the body keep time, with a few exceptions such as stem cells. And they also began to realize that the astrocytes do a lot more than they had thought. Among other things, they secrete and slurp neurotransmitters and help neurons form strengthened synapses to consolidate what we’ve learned. In fact, scientists began to speak of the tripartite synapse, emphasizing the role of an astrocyte in the communication between two neurons.

So for a neuroscientist like Herzog, the obvious question was: What were the astrocytes doing in the SCN? Were they keeping time? And if they were keeping time, how did the astrocyte clocks interact with the neuron clocks?

Herzog answered the first question in 2005 — yes, astrocytes have daily clocks — but then the research got stuck. To figure out what the astrocytes were doing in living networks of cells and in living animals, the scientists had to be able to manipulate them independently of the neurons with which they are entwined. The tools to do this simply didn’t exist.

Now, Herzog’s graduate student Matt Tso, the first author on the paper, has solved the problem. The tools he devised allow astrocytes in the SCN to be independently controlled. Using his toolkit, the lab ran two experiments, altering the astrocyte clocks and monitoring the highly ritualized, daily behavior of wheel-running in mice.

The scientists were surprised by the results, to be published in the April 7 print issue of Current Biology. In both experiments, tweaks to the astrocyte clocks reliably slowed the mouse’s sense of time. “We had no idea they would be that influential,” Tso said.

The scientists are already planning follow-up experiments.

Figuring out how and where these clocks function in the brain and body is important because their influence is ubiquitous. For his part, Herzog is already looking at the connections between circadian rhythm and brain cancer, pre-term birth, manic depression and other diseases.

Astrocytes clock in

A biological clock is a series of interlocking reactions that act somewhat like a biochemical hourglass. An accumulating protein eventually shuts down its own production, much as the sand eventually drains from the top half of the hourglass. But then —through the magic of feedback loops — the biochemical hourglass, in effect, turns itself over and starts again.

At first, scientists were aware only of the clock in the SCN. If it is destroyed in an animal such as a rat, the rat will sleep for the same amount of time but in fits and starts instead of for long periods.

In 2005, Herzog demonstrated that astrocytes, like neurons, have internal clocks. His test subjects made the cover of an issue of the Journal of Neuroscience that year.

But then the genes that make up the biological clock began to be found in many different kinds of cells: lung, heart, liver, and sperm. Hair cells, by the way, prefer to grow in the evening.

So Herzog began to wonder about astrocytes in the SCN. Were they, too, keeping time?

To find out, he coupled a bioluminescent protein to a clock gene and then isolated astrocytes in a glass dish. He found that the astrocytes brightened and dimmed rhythmically, proof that they were keeping time.

The obvious next step was to look at the astrocytes not only in a glass dish but also in SCN slices and in living animals. But that turned out to be easier said than done. “We burned through two postdocs trying to get these experiments to work,” Herzog said.

So it is a technical triumph that Tso was able to make the astrocytes light up when they were expressing clock genes and to add or delete clock genes in the astrocytes while leaving the neurons intact, Herzog said.

To manipulate the astrocytes in the SCN independently of neurons, the scientists needed a way to target the astrocytes alone. The key turned out to a structural protein that helps to give astrocytes their branching structure, here linked to a protein that fluoresces green. Credit: LPDWiki.

As a first step, collaborator Michihiro Mieda from Kanazawa University created a “conditional reporter” that switched on a firefly luciferase whenever a clock gene was being expressed in a cell of interest. Tso delivered the tiny switch to the astrocytes inside a virus.

In slices of a mouse SCN with this reporter in place, the scientists could see that the star-shaped cells were expressing the clock gene in a rhythmic pattern. This proved that astrocytes keep time in living tissue where they are interacting with one another and with neurons, as well as when they are isolated in a dish.

Next, the scientists used the new gene-editing tool CRISPR-Cas9 to delete a clock gene in only the astrocytes of the SCN of living mice. They then monitored the mice for changes in the time they started running on a wheel each day.

Running is an easily measured behavior that provides a reliable indication of the state of the underlying body clock. A mouse in constant darkness will start running on a wheel approximately every 23.7 hours, typically deviating by less than 10 minutes from this schedule.

In this SCN slice, cells expressing an astrocyte-specific structural protein that had been stained red (top right panel) matched up well with cells that had been equipped to fluoresce green when they were expressing a clock gene (middle right panel), demonstrating that the scientists could watch astrocytes tick in the biological clock. Credit: Herzog lab.

“When we deleted the gene in the astrocytes, we had good reason to predict the rhythm would remain unchanged,” Tso said. “When people deleted this clock gene in neurons, the animals completely lost rhythm, which suggests that the neurons are necessary to sustain a daily rhythm.”

Instead, when astrocyte clock was deleted, the SCN clock ran slower. The mice climbed into their wheels one hour later than usual every day.

“This was quite a surprise,” Tso said.

The results of the next experiment were even more exciting for them. The scientists began with a mouse that has a mutation making its clocks run fast and then “rescued” this mutation in astrocytes but not in neurons. This meant that the astrocyte clocks were running at the normal pace but the neuron clocks were still fast.

“We expected the SCN to follow the neurons’ pace. There are 10 times more neurons in the SCN than astrocytes. Why would the behavior follow the astrocytes’? ” Tso said.

But that is exactly what they did. The mice with the restored astrocyte clocks climbed into their wheels two hours later than mice whose astrocytes and neurons were both fast-paced.

Discovery of ‘mini-brains’ could change understanding of pain medication

The body’s peripheral nervous system could be capable of interpreting its environment and modulating pain, neuroscientists have established, after studying how rodents reacted to stimulation.

Until now, accepted scientific theory has held that only the central nervous system – the brain and spinal cord – could actually interpret and analyse sensations such as pain or heat.

The peripheral system that runs throughout the body was seen to be a mainly wiring network, relaying information to and from the central nervous system by delivering messages to the ‘control centre’ (the brain), which then tells the body how to react.

In recent years there has been some evidence of a more complex role for the peripheral nervous system, but this study by Hebei Medical University in China and the University of Leeds highlights a crucial new role for the ganglia, a collection of ‘nodules’.

See how the ganglia in the peripheral system could play a key role in interpreting pain.

Previously these were believed to act only as an energy source for messages being carried through the nervous system. In addition, researchers now believe they also have the ability to act as ‘mini-brains’, modifying how much information is sent to the central nervous system.

The five year study found that nerve cells within the ganglia can exchange information between each other with the help of a signalling molecule called GABA, a process that was previously believed to be restricted to the central nervous system.

The findings are published today in the Journal of Clinical Investigation and have potential future implications for the development of new painkillers, including drugs to target backache and arthritis pain.

Pain relief drugs

Current pain relief drugs are targeted at the central nervous system and often have side effects that can include addiction and tolerance issues.

The new research opens up the possibility of a route for developing non-addictive and non-drowsy drugs, targeted at the peripheral nervous system. Safe therapeutic dosage of these new drugs can also be much higher, potentially resulting in higher efficacy.

Whilst the study showed a rodent’s peripheral nervous system was able to interpret the type of stimulation it was sensing, further research is still needed to understand how sensations are interpreted and whether these results apply to humans.

In addition, the theory would need to be adopted by drug development companies and extensively tested before laboratory and clinical trials of a drug could be carried out. Should the findings be adopted, a timescale of at least 15-20 years might be required to produce a working drug.

Nerve arrangements

Neuroscientist Professor Nikita Gamper, who led the research at both universities, said: “We found the peripheral nervous system has the ability to alter the information sent to the brain, rather than blindly passing everything on to the central nervous system.

“We don’t yet know how the system works, but the machinery is definitely in place to allow the peripheral system to interpret and modify the tactile information perceived by the brain in terms of interpreting pain, warmth or the solidity of objects.

“Further research is needed to understand exactly how it operates, but we have no reason to believe that the same nerve arrangements would not exist in humans.

“When our research team looked more closely at the peripheral system, we found the machinery for neuronal communication did exist in the peripheral nervous system’s structure. It is as if each sensory nerve has its own ‘mini-brain’, which to an extent, can interpret incoming information.”

[…]

Professor Gamper believes the findings may present a challenge to the accepted ‘Gate Control Theory of Pain’. The theory holds that a primary ‘gate’ exists between the peripheral and central nervous systems, controlling what information is sent to the central system.

The study now suggests the transmission of information to the central nervous system must go through another set of gates, or more accurately a process similar to a volume control, where the flow of information can be controlled by the peripheral nervous system.

Brain is 10 times more active than previously measured, UCLA researchers find

Dan Gordon | March 09, 2017

Enter a caption

Shelley Halpain/UC San DiegoUCLA scientists discovered that dendrites (shown here in green) are not just passive conduits for electrical currents between neurons.

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A new UCLA study could change scientists’ understanding of how the brain works — and could lead to new approaches for treating neurological disorders and for developing computers that “think” more like humans.

The research focused on the structure and function of dendrites, which are components of neurons, the nerve cells in the brain. Neurons are large, tree-like structures made up of a body, the soma, with numerous branches called dendrites extending outward. Somas generate brief electrical pulses called “spikes” in order to connect and communicate with each other. Scientists had generally believed that the somatic spikes activate the dendrites, which passively send currents to other neurons’ somas, but this had never been directly tested before. This process is the basis for how memories are formed and stored.

Scientists have believed that this was dendrites’ primary role.

But the UCLA team discovered that dendrites are not just passive conduits. Their research showed that dendrites are electrically active in animals that are moving around freely, generating nearly 10 times more spikes than somas. The finding challenges the long-held belief that spikes in the soma are the primary way in which perception, learning and memory formation occur.

“Dendrites make up more than 90 percent of neural tissue,” said UCLA neurophysicist Mayank Mehta, the study’s senior author. “Knowing they are much more active than the soma fundamentally changes the nature of our understanding of how the brain computes information. It may pave the way for understanding and treating neurological disorders, and for developing brain-like computers.”

Scientists have generally believed that dendrites meekly sent currents they received from the cell’s synapse (the junction between two neurons) to the soma, which in turn generated an electrical impulse. Those short electrical bursts, known as somatic spikes, were thought to be at the heart of neural computation and learning. But the new study demonstrated that dendrites generate their own spikes 10 times more often than the somas.

The researchers also found that dendrites generate large fluctuations in voltage in addition to the spikes; the spikes are binary, all-or-nothing events. The somas generated only all-or-nothing spikes, much like digital computers do. In addition to producing similar spikes, the dendrites also generated large, slowly varying voltages that were even bigger than the spikes, which suggests that the dendrites execute analog computation.

“We found that dendrites are hybrids that do both analog and digital computations, which are therefore fundamentally different from purely digital computers, but somewhat similar to quantum computers that are analog,” said Mehta, a UCLA professor of physics and astronomy, of neurology and of neurobiology. “A fundamental belief in neuroscience has been that neurons are digital devices. They either generate a spike or not. These results show that the dendrites do not behave purely like a digital device. Dendrites do generate digital, all-or-none spikes, but they also show large analog fluctuations that are not all or none. This is a major departure from what neuroscientists have believed for about 60 years.”

Because the dendrites are nearly 100 times larger in volume than the neuronal centers, Mehta said, the large number of dendritic spikes taking place could mean that the brain has more than 100 times the computational capacity than was previously thought.

Recent studies in brain slices showed that dendrites can generate spikes. But it was neither clear that this could happen during natural behavior, nor how often. Measuring dendrites’ electrical activity during natural behavior has long been a challenge because they’re so delicate: In studies with laboratory rats, scientists have found that placing electrodes in the dendrites themselves while the animals were moving actually killed those cells. But the UCLA team developed a new technique that involves placing the electrodes near, rather than in, the dendrites.

Using that approach, the scientists measured dendrites’ activity for up to four days in rats that were allowed to move freely within a large maze. Taking measurements from the posterior parietal cortex, the part of the brain that plays a key role in movement planning, the researchers found far more activity in the dendrites than in the somas — approximately five times as many spikes while the rats were sleeping, and up to 10 times as many when they were exploring.

“Many prior models assume that learning occurs when the cell bodies of two neurons are active at the same time,” said Jason Moore, a UCLA postdoctoral researcher and the study’s first author. “Our findings indicate that learning may take place when the input neuron is active at the same time that a dendrite is active — and it could be that different parts of dendrites will be active at different times, which would suggest a lot more flexibility in how learning can occur within a single neuron.”

The rhythm that makes memories permanent

Scientists at IST Austria identify mechanism that regulates rhythmic brain waves • Inhibition at synapses is the key to make memories permanent

Every time we learn something new, the memory does not only need to be acquired, it also needs to be stabilized in a process called memory consolidation. Brain waves are considered to play an important role in this process, but the underlying mechanism that dictates their shape and rhythm was still unknown. A study now published in Neuron shows that one of the brain waves important for consolidating memory is dominated by synaptic inhibition.

So-called sharp wave ripples (SWRs) are one of three major brain waves coming from the hippocampus. The new study, a cooperation between the research groups of Professors Peter Jonas and Jozsef Csicsvari at the Institute of Science and Technology Austria (IST Austria), found the mechanism that generates this oscillation of neuronal activity in mice. “Our results shed light on the mechanisms underlying this high-frequency network oscillation. As our experiments provide information both about the phase and the location of the underlying conductance, we were able to show that precisely timed synaptic inhibition is the current generator for sharp wave ripples.” explains author Professor Peter Jonas.

When neurons oscillate in synchrony, their electrical activity adds together so that measurements of field potential can pick them up. SWRs are one of the most synchronous oscillations in the brain. Their name derives from their characteristic trace when measuring local field potential: the slow sharp waves have a triangular shape with ripples, or fast field oscillations, added on. SWRs have been suggested to play a key role in making memories permanent. In this study, the researchers wanted to identify whether ripples are caused by a temporal modulation of excitation or of inhibition at the synapse, the connection between neurons. For Professor Jozsef Csicsvari, a pooling of expertise was crucial in answering this question: “SWRs play an important role in the brain, but the mechanism generating them has not been identified so far – probably partly because of technical limitations in the experiments. We combined the Jonas group’s experience in recording under voltage-clamp conditions with my group’s expertise in analyzing electrical signals while animals are behaving. This collaborative effort made unprecedented measurements possible and we could achieve the first high resolution recordings of synaptic currents during SWR in behaving mice.”

The neuroscientists found that the frequency of both excitatory and inhibitory events at the synapse increased during SWRs. But quantitatively, synaptic inhibition dominated over excitation during the generation of SWRs. Furthermore, the magnitude of inhibitory events positively correlated with SWR amplitude, indicating that the inhibitory events are the driver of the oscillation. Inhibitory events were phase locked to individual cycles of ripple oscillations. Finally, the researchers showed that so-called PV+ interneurons – neurons that provide inhibitory output onto other neurons – are mainly responsible for generating SWRs.

The authors propose a model involving two specific regions in the hippocampus, CA1 and CA3. In their model SWRs are generated by a combination of tonic excitation from the CA3 region and phasic inhibition within the CA1 region. Jian Gan, first author and postdoc in the group of Peter Jonas, explains the implications for temporal coding of information in the CA1 region: “In our ripple model, inhibition ensures the precise timing of neuronal firing. This could be critically important for preplay or replay of neuronal activity sequences, and the consolidation of memory. Inhibition may be the crucial player to make memories permanent.”

Study demonstrates role of gut bacteria in neurodegenerative diseases

Research at UofL funded by The Michael J. Fox Foundation shows proteins produced by gut bacteria may cause misfolding of brain proteins and cerebral inflammation

Robert P. Friedland, M.D.

Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) are all characterized by clumped, misfolded proteins and inflammation in the brain. In more than 90 percent of cases, physicians and scientists do not know what causes these processes to occur.

Robert P. Friedland, M.D., the Mason C. and Mary D. Rudd Endowed Chair and Professor of Neurology at the University of Louisville School of Medicine, and a team of researchers have discovered that these processes may be triggered by proteins made by our gut bacteria (the microbiota). Their research has revealed that exposure to bacterial proteins called amyloid that have structural similarity to brain proteins leads to an increase in clumping of the protein alpha-synuclein in the brain. Aggregates, or clumps, of misfolded alpha-synuclein and related amyloid proteins are seen in the brains of patients with the neurodegenerative diseases AD, PD and ALS.

Alpha-synuclein (AS) is a protein normally produced by neurons in the brain. In both PD and AD, alpha-synuclein is aggregated in a clumped form called amyloid, causing damage to neurons. Friedland has hypothesized that similarly clumped proteins produced by bacteria in the gut cause brain proteins to misfold via a mechanism called cross-seeding, leading to the deposition of aggregated brain proteins. He also proposed that amyloid proteins produced by the microbiota cause priming of immune cells in the gut, resulting in enhanced inflammation in the brain.

The research, which was supported by The Michael J. Fox Foundation, involved the administration of bacterial strains of E. coli that produce the bacterial amyloid protein curli to rats. Control animals were given identical bacteria that lacked the ability to make the bacterial amyloid protein. The rats fed the curli-producing organisms showed increased levels of AS in the intestines and the brain and increased cerebral AS aggregation, compared with rats who were exposed to E. coli that did not produce the bacterial amyloid protein. The curli-exposed rats also showed enhanced cerebral inflammation.

Similar findings were noted in a related experiment in which nematodes (Caenorhabditis elegans) that were fed curli-producing E. coli also showed increased levels of AS aggregates, compared with nematodes not exposed to the bacterial amyloid. A research group led by neuroscientist Shu G. Chen, Ph.D., of Case Western Reserve University, performed this collaborative study.

This new understanding of the potential role of gut bacteria in neurodegeneration could bring researchers closer to uncovering the factors responsible for initiating these diseases and ultimately developing preventive and therapeutic measures.

“These new studies in two different animals show that proteins made by bacteria harbored in the gut may be an initiating factor in the disease process of Alzheimer’s disease, Parkinson’s disease and ALS,” Friedland said. “This is important because most cases of these diseases are not caused by genes, and the gut is our most important environmental exposure. In addition, we have many potential therapeutic options to influence the bacterial populations in the nose, mouth and gut.”

Revolutionary method to map the brain at single-neuron resolution is successfully demonstrated

Friday, 19 August 2016 07:00

MAPseq uses RNA sequencing to rapidly and inexpensively find the diverse destinations of thousands of neurons in a single experiment in a single animal

Cold Spring Harbor, NY — Neuroscientists today publish in Neuron details of a revolutionary new way of mapping the brain at the resolution of individual neurons, which they have successfully demonstrated in the mouse brain.

The new method, called MAPseq (Multiplexed Analysis of Projections by Sequencing), makes it possible in a single experiment to trace the long-range projections of large numbers of individual neurons from a specific region or regions to wherever they lead in the brain—in experiments that are many times less expensive, labor-intensive and time-consuming than current mapping technologies allow.

Although a number of important brain-mapping projects are now under way, all of these efforts to obtain “connectomes,” or wiring maps, rely upon microscopes and related optical equipment to trace the myriad thread-like projections that link neurons to other neurons, near and far. For the first time ever, MAPseq “converts the task of brain mapping into one of RNA sequencing,” says its inventor, Anthony Zador, M.D., Ph.D., professor at Cold Spring Harbor Laboratory.

“The RNA sequences, or ‘barcodes,’ that we deliver to individual neurons are unmistakably unique,” Zador explains, “and this enables us to determine if individual neurons, as opposed to entire regions, are tailored to specific targets.”

An injection into a “source” region of the brain contains a viral library encoding a diverse collection of barcode sequences, which are hitched to an engineered protein that is designed to carry the barcode along axonal pathways. The barcode RNA is expressed at high levels and transported into the terminals of axons in the source region where the injection is made. In each neuron, it travels to the point where the axon forms a synapse with a projection from another neuron. (click to enlarge)

“Bulk” labeling methods now widely in use to map brain connections are able to determine that neurons in the “source” region (left side) project to three green-shaded regions (right side), but are not able to distinguish the specific destinations of individual neurons in the source region. MAPseq enables such distinction — in this example, showing that neurons bearing specific “barcodes” (vastly reduced in complexity here for demonstration purposes) carry those barcodes to some of the 3 “destinations” but not necessarily all of them, or the same ones as other neurons in the source region. (click to enlarge)

MAPseq differs from so-called “bulk tracing” methods now in common use, in which a marker—typically a fluorescent protein—is expressed by neurons and carried along their axons. Such markers are good at determining all of the regions where neurons in the source region project to, but they cannot tell scientists that any two neurons in the source region project to the same region, to different regions, or to some of the same regions, and some different ones. That inability to resolve a neuron’s axonal destinations, cell by cell in a given region, is what motivated Zador to come up with a new technique.

One way of explaining the advantage of MAPseq over bulk tracing methods is to imagine being at an international airport, with the intention of getting on a flight to, say, Germany. “If you go to the international terminal, you see a long line of ticket counters,” Zador explains. “If you want to go to Germany, it’s not enough to take any airline at the international terminal. If you stand in line at the counter for Air Chile, you’re probably not going to be able to buy a ticket for Germany.”

“Those many airlines whose counters are adjacent serve many destinations, some of which overlap, some of which are unique. You can print out a map showing all of the foreign countries that all of the airlines serve from your airport, but that doesn’t tell you anything at all about individual airlines and where they go. This is the difference between current labeling methods and MAPseq. The ‘individual airlines’ in my example are adjacent neurons in a part of the brain whose ‘routes’ we want to trace.”

Zador and his team, including Justus Kebschull, a graduate student in his lab who is first author on the Neuron paper introducing the new method, have spent several years working out a technology that enables them to assign unique barcode-like identifiers to large numbers of individual neurons via a single injection in any brain region of interest. Each injection consists of a deactivated virus that has been engineered to contain massive pools of individually unique RNA molecules, each of whose sequence—consisting of 30 “letters,” or nucleotides—is taken up by single neurons. Thirty letters yields many, many times more barcode sequences (1018) than there are neurons in either the mouse or human brain, so this method is especially well suited to the massive complexity problem that brain mapping presents.

An injection into a “source” region of the brain contains a viral library encoding a diverse collection of barcode sequences, which are hitched to an engineered protein that is designed to carry the barcode along axonal pathways. The barcode RNA is expressed at high levels and transported into the terminals of axons in the source region where the injection is made. In each neuron, it travels to the point where the axon forms a synapse with a projection from another neuron. Tests show that the technology works—the barcodes travel reliably and evenly throughout the brain, along the “trunklines” that are the axons, and out to the “branch points” where synapses form.

About two days after one or more injections are made in a region of interest, the brain is dissected and RNA is collected and sequenced. RNA barcodes in the “source” area are now matched with the same barcodes collected in distant parts of the brain.

To demonstrate MAPseq’s capabilities, Zador’s team injected a part of the mouse brain called the locus coeruleus (LC), located in the brain stem. After nearly 2 days, the cortex was divided in 22 slices, dissected and sequenced for RNA barcodes. The sequence readouts were matched with barcodes of cells in the region of the initial injection, establishing specific paths of individual LC neurons. (click to enlarge)

“Sequencing the RNA is a highly efficient, automated process, which makes MAPseq such a potentially radical tool,” Kebschull says. “In addition to the speed and economy of RNA sequencing, it has the great advantage of making it possible for researchers to distinguish between individual neurons within the same region that project to different parts of the brain.”

To demonstrate MAPseq’s capabilities, Zador’s team injected a part of the mouse brain called the locus coeruleus (LC), located in the brain stem. It is the cortex’s sole source of noradrenaline, a hormone that signals surprise. Zador’s team used MAPseq to address an old question: does the “surprise” signal get broadcast everywhere in the cortex, or only to particular places, where, perhaps, it is most needed or relevant?

In their demonstration experiment, only RNA that ended up in the cortex or olfactory bulb was sequenced, along with that of the source region in the LC where the barcodes were originally injected. The team divided the cortex into 22 slices, each about 300 microns thick, and dissected the slices. The results were exciting to the team.

“We found that neurons in the LC have a variety of idiosyncratic projection patterns,” Zador says. “Some neurons project almost exclusively to a single preferred target in the cortex or olfactory bulb. Other neurons project more broadly, although weakly.”

These results, he adds, “are consistent with, and reconcile, previous seemingly contradictory results about LC projections.” The surprise signal can reach most parts of the brain, but there are very specific parts of the brain where the signal is especially focused.

The team showed that results could be obtained in experiments based on one injection in the LC, and also two injections, on opposite sides. Already in progress are experiments in which the entire cortex is being “tiled” with injections. It is hoped this will yield the first connectome of the entire cortex at single-neuron resolution.

“Once we automate the process of using many injections, we think this kind of experiment can be completed by a single person in just a week or two, and at a cost of only a few thousand dollars,” Zador says. “We are very keen on being able to do these kind of studies in a single animal, which will eliminate the past problem of injecting multiple animals to trace multiple neurons, a method that requires one to make a single map based on many brains, each of which is somewhat different.”

Zador’s next goal with MAPseq is to map the brains of animals that model various neurodevelopmental and neuropsychiatric illnesses, to see how gene mutations strongly associated with causality alter the structure of brain circuits, and thus, presumably, brain function.

Study finds brain connections key to reading

Pathways that exist before kids learn to read may determine development of brain’s word recognition area.

Anne Trafton | MIT News Office
August 8, 2016

A new study from MIT reveals that a brain region dedicated to reading has connections for that skill even before children learn to read.

By scanning the brains of children before and after they learned to read, the researchers found that they could predict the precise location where each child’s visual word form area (VWFA) would develop, based on the connections of that region to other parts of the brain.

Neuroscientists have long wondered why the brain has a region exclusively dedicated to reading — a skill that is unique to humans and only developed about 5,400 years ago, which is not enough time for evolution to have reshaped the brain for that specific task. The new study suggests that the VWFA, located in an area that receives visual input, has pre-existing connections to brain regions associated with language processing, making it ideally suited to become devoted to reading.

“Long-range connections that allow this region to talk to other areas of the brain seem to drive function,” says Zeynep Saygin, a postdoc at MIT’s McGovern Institute for Brain Research. “As far as we can tell, within this larger fusiform region of the brain, only the reading area has these particular sets of connections, and that’s how it’s distinguished from adjacent cortex.”

Saygin is the lead author of the study, which appears in the Aug. 8 issue of Nature Neuroscience. Nancy Kanwisher, the Walter A. Rosenblith Professor of Brain and Cognitive Sciences and a member of the McGovern Institute, is the paper’s senior author.

Specialized for reading

The brain’s cortex, where most cognitive functions occur, has areas specialized for reading as well as face recognition, language comprehension, and many other tasks. Neuroscientists have hypothesized that the locations of these functions may be determined by prewired connections to other parts of the brain, but they have had few good opportunities to test this hypothesis.

Reading presents a unique opportunity to study this question because it is not learned right away, giving scientists a chance to examine the brain region that will become the VWFA before children know how to read. This region, located in the fusiform gyrus, at the base of the brain, is responsible for recognizing strings of letters.

Children participating in the study were scanned twice — at 5 years of age, before learning to read, and at 8 years, after they learned to read. In the scans at age 8, the researchers precisely defined the VWFA for each child by using functional magnetic resonance imaging (fMRI) to measure brain activity as the children read. They also used a technique called diffusion-weighted imaging to trace the connections between the VWFA and other parts of the brain.

The researchers saw no indication from fMRI scans that the VWFA was responding to words at age 5. However, the region that would become the VWFA was already different from adjacent cortex in its connectivity patterns. These patterns were so distinctive that they could be used to accurately predict the precise location where each child’s VWFA would later develop.

Although the area that will become the VWFA does not respond preferentially to letters at age 5, Saygin says it is likely that the region is involved in some kind of high-level object recognition before it gets taken over for word recognition as a child learns to read. Still unknown is how and why the brain forms those connections early in life.

Pre-existing connections

Kanwisher and Saygin have found that the VWFA is connected to language regions of the brain in adults, but the new findings in children offer strong evidence that those connections exist before reading is learned, and are not the result of learning to read, according to Stanislas Dehaene, a professor and the chair of experimental cognitive psychology at the College de France, who wrote a commentary on the paper for NatureNeuroscience.

“To genuinely test the hypothesis that the VWFA owes its specialization to a pre-existing connectivity pattern, it was necessary to measure brain connectivity in children before they learned to read,” wrote Dehaene, who was not involved in the study. “Although many children, at the age of 5, did not have a VWFA yet, the connections that were already in place could be used to anticipate where the VWFA would appear once they learned to read.”

The MIT team now plans to study whether this kind of brain imaging could help identify children who are at risk of developing dyslexia and other reading difficulties.

Filed under: fusiform gyrus, reading, Uncategorized, visual word form area Tagged: fusiform gyrus, reading, visual word form area]]>https://neuronsandsynapses.wordpress.com/2016/08/08/scientists-find-area-in-brain-that-is-prewired-for-reading/feed/0neuronrepairNeuroscientists have long wondered why the brain has a region exclusively dedicated to reading — a skill that is unique to humans and only developed about 5,400 years ago.Increased neurogenesis from exercise does not cause forgetting of previously learned taskhttps://neuronsandsynapses.wordpress.com/2016/08/04/increased-neurogenesis-from-exercise-does-not-cause-forgetting-of-previously-learned-task/
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From Vital Record News from Texas A & M University Health Science Center:

Study shows exercise won’t cause you to forget things

Research has found that exercise causes more new neurons to be formed in a critical brain region, and contrary to an earlier study, these new neurons do not cause the individual to forget old memories, according to research by Texas A&M College of Medicine scientists, in the Journal of Neuroscience.

Exercise is well known for its cognitive benefits, thought to occur because it causes neurogenesis, or the creation of new neurons, in the hippocampus, which is a key brain region for learning, memory and mood regulation. Therefore, it was a surprise in 2014 when a research study, published in the journal Science, found that exercise caused mice to forget what they’d already learned.

“It stunned the field of hippocampal neurogenesis,” said Ashok K. Shetty, PhD, a professor in the Texas A&M College of Medicine Department of Molecular and Cellular Medicine, associate director of the Institute for Regenerative Medicine, and research career scientist at the Central Texas Veterans Health Care System. “It was a very well-done study, so it caused some concern that exercise might in some way be detrimental for memory.”

The animal models in the exercise group—in the previous study—showed far more neurogenesis than the control group, but contrary to what one might think, these additional neurons seemed to erase memories that were formed before they started the exercise regimen. To test this, the researchers removed the extra neurons, and the mice suddenly were able to remember again.

“The mice who exercised had a large number of new neurons,” Shetty said, “but somehow that seemed to break down the old connections, making them forget what they knew.”

Shetty and his team decided to replicate this earlier research, using rats instead of mice. Rats are thought to be more like humans physiologically, with more-similar neuronal workings. They found that—luckily for runners everywhere—these animal models showed no such degradation in memories.

“We had completely contradictory findings from the 2014 study,” said Maheedhar Kodali, PhD, a postdoctoral fellow at the Institute for Regenerative Medicine and the first author of this study. “Now we need to study other species to fully understand this phenomenon.”

Shetty and his team trained their animal models to complete a task over the course of four days, followed by several days of memory consolidation by performing the task over and over again. Then, half the trained animal models were put into cages with running wheels for several weeks, while the control group remained sedentary.

The rats who ran further over the course of that time had much greater neurogenesis in their hippocampus, and all rats who had access to a wheel (and therefore ran at least some), had greater neurogenesis than the sedentary group. On an average, they ran about 48 miles in four weeks, and neuron formation doubled in the hippocampus of these animals.

“This is pretty clear evidence that exercise greatly increases neurogenesis in the hippocampus, which has functional implications,” Kodali said. “Neurogenesis is important for maintaining normal mood function, as well as for learning and creating new memories.” This connection may help explain why exercise is an effective antidepressant.

Importantly, despite differing levels of increased neurogenesis, both moderate runners and brisk runners (those who ran further than average) in Shetty’s study showed the same ability as the sedentary runners to recall the task they learned before they began to exercise. This means even a large amount of running (akin to people who perform significant amount of exercise on a daily basis) doesn’t interfere with the recall of memory.

Minding the Pulse of Memory Consolidation

Sleep is essential for memory. Mounting evidence continues to support the notion that the nocturnal brain replays, stabilizes, reorganizes, and strengthens memories while the body is at rest. Recently, one particular facet of this process has piqued the interest of a growing group of neuroscientists: sleep spindles. For years these brief bursts of brain activity have been largely ignored. Now it seems that examining these neuronal pulses could help researchers better understand—perhaps even treat—cognitive impairments.

It appears they are also a fundamental part of the process by which the human brain consolidates memories during sleep.

A memory formed during the day is stored temporarily in the hippocampus, before being spontaneously replayed during the night. Information about the memory is distributed out and integrated into the neocortex through an orchestra of slow-waves, spindles, and rapid hippocampal ripples. Spindles, it seems, could be a guiding force—providing the plasticity and coordination needed for this delicate, interregional transfer of information.

“Spindles appear to play a central role whenever memories during sleep are undergoing transformation that might be necessary to integrate them into neocortical long-term storage networks,” Jan Born, a professor of behavioral neurobiology of the University of Tübingen, told The Scientist during a conference dedicated to sleep spindles held in Budapest in May.

Fewer spindles, therefore, would be expected to coincide with a breakdown in memory consolidation.

WASHINGTON — Resveratrol, given to Alzheimer’s patients, appears to restore the integrity of the blood-brain barrier, reducing the ability of harmful immune molecules secreted by immune cells to infiltrate from the body into brain tissues, say researchers at Georgetown University Medical Center. The reduction in neuronal inflammation slowed the cognitive decline of patients, compared to a matching group of placebo-treated patients with the disorder.

The laboratory data provide a more complete picture of results from a clinical trial studying resveratrol in Alzheimer’s disease that was first reported in 2015. The new findings will be presented at the Alzheimer’s Association International Conference 2016 in Toronto on July 27th.

The Alzheimer’s disease brain is damaged by inflammation, thought to be due to a reaction to the buildup of abnormal proteins, including Abeta40 and Abeta42, linked to destruction of neurons. Researchers believe that heightened inflammation — which was historically thought to come only from “resident” brain immune cells — worsens the disease. According to the researchers, this study suggests that some of the immune molecules that can cause inflammation in the blood can enter the brain through a leaky blood-brain barrier.

“These findings suggest that resveratrol imposes a kind of crowd control at the border of the brain. The agent seems to shut out unwanted immune molecules that can exacerbate brain inflammation and kill neurons,” says neurologist Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherapeutics Program. “These are very exciting findings because it shows that resveratrol engages the brain in a measurable way, and that the immune response to Alzheimer’s disease comes, in part, from outside the brain.”

Resveratrol is a naturally occurring compound found in foods such as red grapes, red wine, raspberries and dark chocolate. GUMC researchers, led by R. Scott Turner, MD, PhD, tested the substance in 119 patients, the largest nationwide phase II clinical trial to study high-dose pure synthetic (pharmaceutical-grade) resveratrol in individuals with mild to moderate Alzheimer’s. The study was published Sept. 11, 2015 in Neurology.

The new part of the resveratrol study examines specific molecules in the cerebrospinal fluid (CSF) taken from participants with biomarker-confirmed Alzheimer’s disease — 19 were given a placebo, and 19 treated daily for a year with resveratrol, equivalent to the amount found in about 1,000 bottles of red wine.

Previous studies with animals found that age-related diseases–including Alzheimer’s — can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake). The researchers studied resveratrol because it mimics the effects of caloric restriction by also activating proteins called sirtuins.

In this new study, Moussa and Turner found that treated patients had a 50 percent reduction in matrix metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid. MMP-9 is decreased when sirtuin1 (SIRT1) is activated. High levels of MMP-9 cause a breakdown in the blood-brain barrier, allowing proteins and molecules from the body to enter the brain. Normally low MMP-9 levels maintain the barrier, say the researchers.

“These new findings are exciting because they increase our understanding of how resveratrol may be clinically beneficial to individuals with Alzheimer’s disease. In particular, they point to the important role of inflammation in the disease, and the potent anti-inflammatory effects of resveratrol,” says Turner, director of GUMC’s Memory Disorders Program and co-director of the Translational Neurotherapeutics Program.

They also found that resveratrol increased the level of molecules linked to a long-term beneficial or “adaptive” immune reaction, suggesting involvement of inflammatory cells that are resident in the brain, says Moussa. “This is the kind of immune response you want — it is there to remove and degrade neurotoxic proteins.”

“A puzzling finding from the resveratrol study (as well as immunotherapy strategies for Alzheimer’s under investigation) is the greater shrinkage of the brain found with treatment. These new findings support the notion that resveratrol decreases swelling that results from inflammation in Alzheimer’s brain,” says Turner. “This seemingly paradoxical effect is also found with many of the drugs that are beneficial for patients with multiple sclerosis — another brain disease characterized by excessive inflammation.”

Flipping a protein switch to illuminate brain functions

Japan — What goes on inside the brain when we learn new things? Much still remains wrapped in mystery, but scientists have found a way to examine this at the molecular level.

Researchers in Japan have engineered an artificial switch that could let scientists turn individual neurotransmitter receptors on and off. Shedding light on these receptors’ role in memory formation could contribute to the development of new drugs for neurological diseases, including Alzheimer’s, Parkinson’s, and ALS.

Neurotransmitter receptors help relay information from neuron to neuron. “Investigating the functions of various neurotransmitter receptors could be immensely useful, because a majority of drugs on the market target them,” says lead author Ryou Kubota of Kyoto University. “But with so many similarly-structured proteins in the membrane, it’s been extremely difficult to determine which receptors do what.

“Discovering the functions of each neurotransmitter receptor in the brain could help us understand how we learn and acquire memory; to do that, it’s crucial to be able to activate them selectively.”

In the study, published in Nature Chemistry, the team succeeded in selectively activating glutamate receptors, which are pacman-shaped neutrotransmitter receptors known to be involved in memory formation.

Membrane proteins change in shape when they become active. For pacman-shaped glutamate receptors, activation happens when they “bite”. The team genetically engineered glutamate receptors to include switches forcing activation and deactivation. “The switch comes in the shape of two ‘clips’ on what would be the upper and lower lips of pacman,” explains Kubota. “When we tell the clips to bind together, we force the glutamate receptor to activate.”

The current study only reports outcomes with glutamate receptors, but the authors say that their method also shows promise with other kinds of membrane receptors. “Even within glutamate receptors there are subtypes, and within those subtypes there are further distinctions. This time we were able to distinguish and selectively activate each subtype,” remarks Kubota.

Natural Molecule Could Improve Parkinson’s

A natural molecule shows benefit in a preliminary clinical trial for Parkinson’s Disease

Released:16-Jun-2016 2:00 PM EDT

Thomas Jefferson University Brain scans of a representative patient showing Dopamine transporter binding (red) before and after 3-month NAC treatment.

Newswise — (PHILADELPHIA) — The natural molecule, n-acetylcysteine (NAC), with strong antioxidant effects, shows potential benefit as part of the management for patients with Parkinson’s disease, according to a study published today in the journal PLOS ONE. Combining clinical evaluations of a patient’s mental and physical abilities with brain imaging studies that tracked the levels of dopamine, the lack of which is thought to cause Parkinson’s, doctors from the Departments of Integrative Medicine, Neurology, and Radiology, at Thomas Jefferson University showed that patients receiving NAC improved on both measures.

Current treatments for Parkinson’s disease are generally limited to temporarily replacing dopamine in the brain as well as some medications designed to slow the progression of the disease process. Recently, researchers have shown that oxidative stress in the brain may play a critical role in the Parkinson’s disease process, and that this stress also lowers levels of glutathione, a chemical produced by the brain to counteract oxidative stress. Studies in brain cells showed that NAC helps reduce oxidative damage to neurons by helping restore the levels of the antioxidant glutathione. NAC is an oral supplement that can be obtained at most nutrition stores, and interestingly also comes in an intravenous form which is used to protect the liver in acetaminophen overdose.

“This study reveals a potentially new avenue for managing Parkinson’s patients and shows that n-acetylcysteine may have a unique physiological effect that alters the disease process and enables dopamine neurons to recover some function,” said senior author on the paper Daniel Monti, M.D., M.B.A., Director of the Myrna Brind Center of Integrative Medicine, and the Brind-Marcus Center of Integrative Medicine at Thomas Jefferson University.

In this study, Parkinson’s patients who continued their current standard of care treatment, were placed into two groups. The first group received a combination of oral and intravenous (IV) NAC for three months. These patients received 50mg/kg NAC intravenously once per week and 600mg NAC orally 2x per day on the non IV days. The second group, the control patients, received only their standard of care for Parkinson’s treatment. Patients were evaluated initially, before starting the NAC and then after three months of receiving the NAC while the control patients were simply evaluated initially and three months later. The evaluation consisted of standard clinical measures such as the Unified Parkinson’s Disease Rating Scale (UPDRS), a survey administered by doctors to help determine the stage of disease, and a brain scan via DaTscan SPECT imaging, which measures the amount of dopamine transporter in the basal ganglia, the area most affected by the Parkinson’s disease process. Compared to controls, the patients receiving NAC had improvements of 4-9 percent in dopamine transporter binding and also had improvements in their UPDRS score of about 13 percent.

“We have not previously seen an intervention for Parkinson’s disease have this kind of effect on the brain,” said first author and neuro-imaging expert Andrew Newberg, M.D., Professor at the Sidney Kimmel Medical College at Jefferson and Director of Research at the Myrna Brind Center of Integrative Medicine. The investigators hope that this research will open up new avenues of treatment for Parkinson’s disease patients.

A range of diseases — from diabetes to cardiovascular disease, and from Alzheimer’s disease to attention deficit hyperactivity disorder — are linked to changes to genes in the brain. A new study by UCLA life scientists has found that hundreds of those genes can be damaged by fructose, a sugar that’s common in the Western diet, in a way that could lead to those diseases.

However, the researchers discovered good news as well: An omega-3 fatty acid known as docosahexaenoic acid, or DHA, seems to reverse the harmful changes produced by fructose.

“DHA changes not just one or two genes; it seems to push the entire gene pattern back to normal, which is remarkable,” said Xia Yang, a senior author of the study and a UCLA assistant professor of integrative biology and physiology. “And we can see why it has such a powerful effect.”

DHA occurs naturally in the membranes of our brain cells, but not in a large enough quantity to help fight diseases.

“The brain and the body are deficient in the machinery to make DHA; it has to come through our diet,” said Fernando Gomez-Pinilla, a UCLA professor of neurosurgery and of integrative biology and physiology, and co-senior author of the paper.

Reed Hutchinson/UCLA Xia Yang and Fernando Gomez-Pinilla

DHA strengthens synapses in the brain and enhances learning and memory. It is abundant in wild salmon (but not in farmed salmon) and, to a lesser extent, in other fish and fish oil, as well as walnuts, flaxseed, and fruits and vegetables, said Gomez-Pinilla, who also is a member of UCLA’s Brain Injury Research Center.

Americans get most of their fructose in foods that are sweetened with high-fructose corn syrup, an inexpensive liquid sweetener made from corn starch, and from sweetened drinks, syrups, honey and desserts. The Department of Agriculture estimates that Americans consumed an average of about 27 pounds of high-fructose corn syrup in 2014. Fructose is also found is in most baby food and in fruit, although the fiber in fruit substantially slows the body’s absorption of the sugar — and fruit contains other healthy components that protect the brain and body, Yang said.

To test the effects of fructose and DHA, the researchers trained rats to escape from a maze, and then randomly divided the animals into three groups. For the next six weeks, one group of rats drank water with an amount of fructose that would be roughly equivalent to a person drinking a liter of soda per day. The second group was given fructose water and a diet rich in DHA. The third received water without fructose and no DHA.

After the six weeks, the rats were put through the maze again. The animals that had been given only the fructose navigated the maze about half as fast than the rats that drank only water — indicating that the fructose diet had impaired their memory. The rats that had been given fructose and DHA, however, showed very similar results to those that only drank water — which strongly suggests that the DHA eliminated fructose’s harmful effects.

Other tests on the rats revealed more major differences: The rats receiving a high-fructose diet had much higher blood glucose, triglycerides and insulin levels than the other two groups. Those results are significant because in humans, elevated glucose, triglycerides and insulin are linked to obesity, diabetes and many other diseases.

The research team sequenced more than 20,000 genes in the rats’ brains, and identified more than 700 genes in the hypothalamus (the brain’s major metabolic control center) and more than 200 genes in the hippocampus (which helps regulate learning and memory) that were altered by the fructose. The altered genes they identified, the vast majority of which are comparable to genes in humans, are among those that interact to regulate metabolism, cell communication and inflammation. Among the conditions that can be caused by alterations to those genes are Parkinson’s disease, depression, bipolar disorder, and other brain diseases, said Yang, who also is a member of UCLA’s Institute for Quantitative and Computational Biosciences.

Of the 900 genes they identified, the researchers found that two in particular, called Bgn and Fmod, appear to be among the first genes in the brain that are affected by fructose. Once those genes are altered, they can set off a cascade effect that eventually alters hundreds of others, Yang said.

That could mean that Bgn and Fmod would be potential targets for new drugs to treat diseases that are caused by altered genes in the brain, she added.

The research also uncovered new details about the mechanism fructose uses to disrupt genes. The scientists found that fructose removes or adds a biochemical group to cytosine, one of the four nucleotides that make up DNA. (The others are adenine, thymine and guanine.) This type of modification plays a critical role in turning genes “on” or “off.”

The research is published online in EBioMedicine, a journal published jointly by Cell and The Lancet. It is the first genomics study of all the genes, pathways and gene networks affected by fructose consumption in the regions of the brain that control metabolism and brain function.

Previous research led by Gomez-Pinilla found that fructose damages communication between brain cells and increases toxic molecules in the brain; and that a long-term high-fructose diet diminishes the brain’s ability to learn and remember information.

“Food is like a pharmaceutical compound that affects the brain,” said Gomez-Pinilla. He recommends avoiding sugary soft drinks, cutting down on desserts and generally consuming less sugar and saturated fat.

Although DHA appears to be quite beneficial, Yang said it is not a magic bullet for curing diseases. Additional research will be needed to determine the extent of its ability to reverse damage to human genes.

“We pitted drawing against a number of other known encoding strategies, but drawing always came out on top,” said the study’s lead author, Jeffrey Wammes, PhD candidate in the Department of Psychology. “We believe that the benefit arises because drawing helps to create a more cohesive memory trace that better integrates visual, motor and semantic information.”

The study, by Wammes, along with fellow PhD candidate Melissa Meade and Professor Myra Fernandes, presented student participants with a list of simple, easily drawn words, such as “apple.” The students were given 40 seconds to either draw the word, or write it out repeatedly. They were then given a filler task of classifying musical tones to facilitate the retention process. Finally, the researchers asked students to freely recall as many words as possible from the initial list in just 60 seconds.

“We discovered a significant recall advantage for words that were drawn as compared to those that were written,” said Wammes. “Participants often recalled more than twice as many drawn than written words. We labelled this benefit ‘the drawing effect,’ which refers to this distinct advantage of drawing words relative to writing them out.”

In variations of the experiment in which students drew the words repeatedly, or added visual details to the written letters, such as shading or other doodles, the results remained unchanged. Memory for drawn words was superior to all other alternatives. Drawing led to better later memory performance than listing physical characteristics, creating mental images, and viewing pictures of the objects depicted by the words.

“Importantly, the quality of the drawings people made did not seem to matter, suggesting that everyone could benefit from this memory strategy, regardless of their artistic talent. In line with this, we showed that people still gained a huge advantage in later memory, even when they had just 4 seconds to draw their picture,” said Wammes.

While the drawing effect proved reliable in testing, the experiments were conducted with single words only. Wammes and his team are currently trying to determine why this memory benefit is so potent, and how widely it can be applied to other types of information.

Sussex study reveals brain mechanism for creating durable memories

Dr Chris Bird and his team identified the brain areas whose pattern of activation matched significantly while watching a video and remembering that same video.

Dr Chris Bird and his team identified the brain areas whose pattern of activation matched significantly while watching a video and remembering that same video.

Rehearsing information immediately after being given it may be all you need to make it a permanent memory, a University of Sussex study suggests.

Psychologists found that the same area of the brain activated when laying down a memory is also activated when rehearsing that memory.

The findings, published on 27 October 2015 in the Journal of Neuroscience, have implications for any situation in which accurate recall of an event is critical, such as witnessing an accident or crime.

The study showed that the brain region known as the posterior cingulate – an area whose damage is often seen in those with Alzheimer’s – plays a crucial role in creating permanent memories.

This region not only helps us to recall the episodic details of an event but also integrates the memory into our knowledge and understanding, which makes it resistant to forgetting.

The study involved showing participants 26 short videos of clips taken from YouTube of around 40 seconds in length with a narrative element. For example, one called “nasty neighbours” depicted two men playing practical jokes on each other.

For 20 of the videos, the participants were given around 40 seconds after each video to relate either in their heads or out loud details of the video. For the remaining six videos, this rehearsal period was not given.

Up to two weeks later, participants were still able to recall many details of the videos they had rehearsed, whereas the non-rehearsed videos were largely forgotten.

MRI scans revealed that the same area of the brain – the posterior cingulate – was most associated with the benefits of rehearsal. Here, the degree to which brain activity matched when watching and rehearsing the videos predicted how well the videos were remembered a whole week later.

Lead researcher Dr Chris Bird said: “We know that recent memories are susceptible to being lost until a period of consolidation has elapsed. In this study we have shown that a brief period of rehearsal has a huge effect on our ability to remember complex, lifelike events over periods of 1-2 weeks.

“We have also linked this rehearsal effect to processing in a particular part of the brain – the posterior cingulate.

“The findings have implications for any situation where accurate recall of an event is critical, such as witnessing an accident or crime. Memory for the event will be significantly improved if the witness rehearses the sequence of events as soon as possible afterwards.”

Brain consolidates memory with three-step brainwave

Date of news: 21 September 2015

Our long-term memory is consolidated when we sleep. Short-term memory traces in the hippocampus, an area deep in the brain, are then relocated to more outer parts of the brain (neocortex). An international team of neuroscientists, among who Mathilde Bonnefond and Til Ole Bergmann from the Donders Institute at Radboud Universiy, now shows how a three-step brain oscillation plays an important part in that process. Nature Neuroscience publishes the results on September 21st.

Bonnefond and Bergmann specialize in research on oscillations: waves of brain activity. ‘Non-rapid eye movement (NREM) sleep is responsible for the memory consolidation during our sleep’, Bonnefond explains. ‘NREM is known for its very slow oscillations (SOs). Other types of oscillations are hidden inside these SOs. We discovered that three types of oscillations are nested inside each other in the hippocampus and have a joint function.’

Slow waves, spindles and ripples

Slow oscillations only happen about once per second (~0.75 Hz). In a specific time frame within these SOs, Bergmann, Bonnefond and their colleagues found clusters of oscillations of an intermediate speed: the so called spindles which happen about 15 times per second (12 – 16 Hz). And within these spindles, they found clusters of superfast oscillations called ripples, which happen about 90 times per second (80 – 100 Hz), and which reflect the local reactivation of the memory trace to be shuttled to the cortex.

To summarize: SOs contain spindles, which in their turn contain ripples. ‘Earlier studies only coupled these oscillation types in pairs’, Bonnefond explains. ‘But now, we see that SOs, spindles and ripples are functionally coupled in the hippocampus. And we hypothesize that they provide fine-tuned temporal frames for the transfer of memory traces to the neocortex.’

Epilepsy

The group of researchers investigated the process in human epilepsy patients during natural sleep. Doctors were looking for the brain areas responsible for their epilepsy, and the current research was done at the same time: with special electrodes, the researchers recorded oscillations from inside the brain. Bonnefond: ‘This was a great opportunity to investigate the hippocampus, since it’s difficult to measure deep brain regions with classical electrophysiological techniques, that measure from outside the skull.’

The patients did not have to remember any specific information. ‘You’re consolidating memories every night, so we investigated the process in general. The next step would be to link these clustered oscillations to specific memories.’

Cognitive deficits are a common disabling consequence of brain injury that affect emotional, social and occupational functioning. As impaired memory after TBI is a result of impaired learning, rehabilitative interventions need to address the deficit in learning. This study examined the efficacy of the mSMT, a cognitive intervention, in the TBI population. Kessler researchers previously found the mSMT intervention effective in the population with multiple sclerosis.

Of the 69 participants with moderate to severe TBI enrolled in the study, 35 were assigned to the treatment group and 34 to the placebo group. All underwent neuropsychological assessments before and after treatment and at 6-month followup. Participants in the treatment group were randomized to a booster session or non-booster session group. The treatment group received the mSMT, a 10-session memory retraining protocol. The placebo group underwent memory exercises without. A significant effect was found in the treatment group; no persistent effect was seen in the treatment cohort that had booster sessions of mSMT.

“We found that memory, as assessed with standard memory tests, improved in the treatment group. Treated participants also showed an improvement in everyday functioning,” said Dr. Chiaravalloti, director of Neuroscience & Neuropsychology and TBI Research at Kessler Foundation. “This extends the Class 1 evidence for efficacy of the mSMT to people with moderate to severe TBI. Further study is needed to develop strategies for extending the positive effects of this cognitive intervention in rehabilitative care.”

The mSMT protocol has been translated into Spanish and is being used in the U.S., Mexico and Argentina. A Chinese translation has also been completed for use in upcoming studies.

Surprised? Cholinergic neurons send brain-wide broadcasts enabling us to learn from the unexpected

Thursday, 27 August 2015 13:00 |

Cold Spring Harbor, NY – When a large combat unit, widely dispersed in dense jungle, goes to battle, no single soldier knows precisely how his actions are affecting the unit’s success or failure. But in modern armies, every soldier is connected via an audio link that can instantly receive broadcasts – reporting both positive and negative surprises – based on new intelligence. The real-time broadcasts enable dispersed troops to learn from these reports and can be critical since no solider has an overview of the entire unit’s situation.

Research by Kepecs and colleagues indicates that cholinergic neurons broadcast messages to the rest of the brain when mice encounter unexpected things — things they welcome (depicted here as food, right side) and things they fear (here, a predator, left side). “The fact something is unexpected, and knowing the degree to which it is, is an obvious advantage to the individual,” Kepecs says, suggesting why such real-time alerts may have evolved. credit: Julia Kuhl, CSHL

Similarly, as neuroscientists at Cold Spring Harbor Laboratory (CSHL) have just discovered, there are a set of dedicated neurons in the basal forebrain that broadcast a message throughout the cerebral cortex, rapidly informing multiple distributed subregions of any surprising rewards or punishments – what scientists call reinforcers.

The neurons in question are cholinergic, and the team, led by Associate Professor Adam Kepecs, has succeeded in recording their activity for the first time in behaving animals (mice).

Cholinergic neurons form one of the brain’s several neuromodulatory systems – they send signals in the form of the neurotransmitter acetylcholine to broad swaths of the brain. Although they have been thought to play an important role in arousal, attention and learning, their precise role in behavior has remained mysterious – in part, because of the technical difficulty in recording from them in vivo. Degeneration and loss of cholinergic neurons in the basal forebrain has been implicated in Alzheimer’s disease, age-related cognitive decline, and other cognitive disorders and dementias.

In a paper published online today in Cell, Kepecs and colleagues report on how central cholinergic neurons function, using optogenetic neuron identification —a technique in which mouse neurons are genetically engineered to respond to light. “These are very, very, difficult-to-find neurons, and they form an incredibly important system in the brain,” Kepecs says. “Until recently we didn’t have the techniques to approach this system with the precision required.”

Once they identified cholinergic neurons, the team recorded their activity while mice performed a sound detection task requiring sustained attention.Depending on whether their response was correct or not, mice were either rewarded with drop of water or “punished” with a mild puff of air to their face. Postdoctoral fellow Balazs Hangya of the Kepecs lab discovered that these neurons respond to reward and punishment, with unusual speed and precision, taking only a few thousandths-of-a-second.

To explain the responses researchers constructed a computational model which revealed that the modulation of the signal strength was proportional to how unexpected or surprising the mice found the reward or punishment. According to the model, if the mice were certain their response was correct, the reward generated a weak signal. But if they were unsure, the reward came as more of a surprise and generated a stronger cholinergic signal. “This suggests to us that it’s not really about punishment, per se, but it’s simply that punishment usually is more surprising,” Kepecs says.

Kepecs suggests that cholinergic broadcasts to the cortex would be useful in boosting plasticity, allowing flexibility in neuronal connections that makes learning possible. Whether the surprise registers an outcome or event that was better or worse than expected, the fact it was unexpected, and the degree to which it was, is an obvious advantage to the individual – as, indeed, constant intelligence is to soldiers in the unit enmeshed in jungle combat.

Astrocytes found to play a key role in regulating neural networks

August 14, 2015 by Bob Yirka

(Medical Xpress)—A small team of researchers with members from research centers in Spain and the U.S. has found that astrocyes appear to play a previously unknown key role in regulating neural networks in mouse brains. In their paper published in the journal Science, the team describes their study of a type of glial cell in a certain part of the mouse brain, and what they learned about neural networks in doing so. Aryn Gittis and Daniel Brasier with Carnegie Mellon University offer a Perspective piece on the work done by the team and describe possible implications of their findings.

Glial cells exist wherever there are neural cells—they surround neurons providing support for them and also serve as spacers, keeping the neurons apart. They are the most numerous cells in the nervous system. One type of glial cell, the star shaped astrocytes, are known to be active participants in neural communications via the transmission of gliotransmitters. In this new effort, the research team learned more about the role astrocytes play in neural communications and in so doing discovered that under certain circumstances when astrocytes activate one neuron, the responsiveness of another was enhanced. They also found that under other circumstances, the opposite could occur, when one neuron was caused to be excited, another nearby was simultaneously suppressed.

To learn more about the role astrocytes play in neural networks, the researchers used transgenic mouse lines fluorescently to identify communications between them and what are known as medium spiny neurons, located in the striatum—what they really wanted to know though, was whether certain astrocytes couple with certain neurons, or whether there are less specific couplings that occur. A closer look using triple whole-cell electrical recordings from two of the heterotypic neurons and a single astrocyte suggested the former—they apparently only communicate with specific subtypes of adjacent neurons.

Working long hours linked to higher risk of stroke

20 August 2015

Working 55 hours or more per week is linked to a 33% greater risk of stroke and a more modest (13%) increased risk of developing coronary heart disease compared with working a standard 35 to 40 hour week, according to the largest study in this field so far, led by UCL and published in The Lancet.

Professor Mika Kivimäki (UCL Epidemiology & Public Health) and colleagues did a systematic review and meta-analysis of published studies and unpublished individual-level data examining the effects of longer working hours on cardiovascular disease up to August 20, 2014.

Analysis of data from 25 studies involving 603,838 men and women from Europe, the USA, and Australia who were followed for an average of 8.5 years, found a 13% increased risk of incident coronary heart disease (a new diagnosis, hospitalisation, or death) in people working 55 hours or more per week compared with those putting in a normal 35 to 40 hour week, even after taking into account risk factors including age, sex, and socioeconomic status.

Analysis of data from 17 studies involving 528,908 men and women who were followed up for an average of 7.2 years, found a 1.3 times higher risk of stroke in individuals working 55 hours or more a week compared with those working standard hours. This association remained even after taking into account health behaviours such as smoking, alcohol consumption, and physical activity, and standard cardiovascular risk factors including high blood pressure and high cholesterol.

Importantly, the researchers found that the longer people worked, the higher their chances of a stroke. For example, compared with people who worked standard hours, those working between 41 and 48 hours had a 10% higher risk of stroke, and those working 49 to 54 hours had a 27% increased risk of stroke.

Although the causal mechanisms of these relationships need to be better understood, the authors suggest that increasing health-risk behaviors, such as physical inactivity and high alcohol consumption, as well as repetitive triggering of the stress response, might increase the risk of stroke.

Scientists Uncover a Difference Between the Sexes

Sex does matter: key molecular process in brain is different in males and females

EVANSTON, Ill. — Male and female brains operate differently at a molecular level, a Northwestern University research team reports in a new study of a brain region involved in learning and memory, responses to stress and epilepsy.

Many brain disorders vary between the sexes, but how biology and culture contribute to these differences has been unclear. Now Northwestern neuroscientists have found an intrinsic biological difference between males and females in the molecular regulation of synapses in the hippocampus. This provides a scientific reason to believe that female and male brains may respond differently to drugs targeting certain synaptic pathways.

“The importance of studying sex differences in the brain is about making biology and medicine relevant to everyone, to both men and women,” said Catherine S. Woolley, senior author of the study. “It is not about things such as who is better at reading a map or why more men than women choose to enter certain professions.”

Among their findings, the scientists found that a drug called URB-597, which regulates a molecule important in neurotransmitter release, had an effect in females that it did not have in males. While the study was done in rats, it has broad implications for humans because this drug and others like it are currently being tested in clinical trials in humans.

“Our study starts to put some specifics on what types of molecular differences there are in male and female brains,” Woolley said.

[…]

“We don’t know whether this finding will translate to humans or not,” Woolley said, “but right now people who are investigating endocannabinoids in humans probably are not aware that manipulating these molecules could have different effects in males and females.”

Specifically, Woolley and her research team found that in female brains the drug URB-597 increased the inhibitory effect of a key endocannabinoid in the brain, called anandamide, causing a decrease in the release of neurotransmitters. In male brains, the drug had no effect. (The difference is not related to circulating reproductive hormones.)

The subject of many clinical trials, endocannabinoids are molecules that help regulate the amount of certain neurotransmitters released at synapses, the gap between neurons. These molecules are involved in a variety of physiological processes including memory, motivational state, appetite and pain as well as in epilepsy, a neurological disorder. (Their name comes from the fact that endocannabinoids activate the same neural receptors as the active ingredient in marijuana.)

Understanding what controls the synthesis, release and breakdown of endocannabinoids has broad implications both for normal and pathological brain function, Woolley said. This study contributes an important piece of knowledge.

For 20 years, Woolley actively avoided studying sex differences in the brain until her own data showed her that differences between females and males were real. Her discovery, reported in 2012, that estrogens decreased inhibitory synaptic transmission in the brains of female rats but not in males, changed her thinking.

“Being a scientist is about changing your mind in the face of new evidence,” Woolley said. “I had to change my mind in the face of this evidence.”

Building on these earlier findings, Woolley and her team used a series of electrophysiological and biochemical studies to pinpoint what causes this effect. The researchers found the difference between males and females lies in the interaction between the molecules ERalpha and mGluR1. Details of the molecular pathway are reported in the new study.

To find out what is the same and what is different between males and females, scientists need to study both sexes, Woolley maintains. Currently, about 85 percent of basic neuroscience studies are done in male animals, tissues or cells.

“We are not doing women — and specifically women’s health — any favors by pretending that things are the same if they are not,” Woolley said. “If the results of research would be different in female animals, tissues and cells, then we need to know. This is essential so that we can find appropriate diagnoses, treatments and, ultimately, cures for disease in both sexes.”

Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.

Omega-3, a fatty acid found in oily fish, may prevent the onset of schizophrenia and other psychotic disorders long after being consumed, according to a study released Tuesday.

Up to seven years after taking omega-3 supplements for 12 weeks, young people at “ultra-high” risk were less likely to have suffered the debilitating condition than a control group given a placebo, reported the study.

Schizophrenia is characterised by delusions and hallucinations, including hearing voices and seeing things that do not really exist.

It typically emerges during adolescence or early adulthood, either abruptly or gradually. There is no cure. Current treatment focuses on managing symptoms.

Scientists have long known that patients with schizophrenia exhibit reduced levels of polyunsaturated fatty acid—specifically, omega-3 and omega 6—in cell membranes.

Nearly a decade ago, researchers led by Paul Amminger at the University of Melbourne showed in clinical trials that ingesting the fatty acid delayed a first episode of psychotic disorder in high-risk subjects by up to year.

In a follow up study, published in Nature Communications, Amminger and colleagues report that, nearly seven years later, only 10 percent of the omega-3 group developed psychosis compared to 40 percent in the placebo group.

“We show that omega-3 significantly reduced the risk of progression to psychotic disorder during the entire follow-up period,” the study concluded.

Common medications could delay brain injury recovery

Drugs used to treat common complaints could delay the recovery of brain injury patients according to research led by University of East Anglia (UEA) scientists working with other UK universities including Aston and the NHS, published today in Brain Injury.

Prescribed for up to 50 per cent of older people, medications with anticholinergic properties are used to treat a broad range of common conditions including bladder problems, depression and insomnia.

Anticholinergics are already known to have side effects such as temporary cognitive impairment, dizziness and confusion. But their effects on people with pre-existing brain and spinal injuries have not been investigated until now.

Medications with anti-cholinergic properties are often used on neuro-rehabilitation units frequently to manage symptoms from urinary incontinence to pain.

The study of 52 patients with acquired brain or spinal injury at a neuro-rehabilitation unit showed that the average length of stay was longer in patients with a higher level of anticholinergic drugs in their system, known as the anticholinergic drug burden, or ACB.

Results showed that the change in ACB correlated directly to the length of hospital stay. A higher ACB score on discharge, compared with on admission, was associated with a longer stay in hospital and a lower ACB on discharge saw on average a shorter stay. The team cautioned however that as an observational study, cause-and-effect relationship cannot be implied.

Dr Chris Fox, Professor of Clinical Psychiatry at the Norwich Medical School at UEA and lead author on the paper, said: “The findings suggest there may be a statistically significant relationship between ACB score and length of stay in a neuro-rehabilitation unit following traumatic brain or spinal cord injury”.

He added: “This pilot study demonstrates the need for larger studies to confirm the results and need for further investigation into what long-term effects these common medications are having on the recovery of these patients.”

“While medications with ACB are often needed to treat common complications of brain or spinal cord injuries, cognitive impairment due to the medication may adversely affect a patient’s ability to engage in the rehabilitation process, potentially increasing their length of stay in hospital.”

Length of patient stay is used a performance indicator for hospitals, with financial incentives in place for units to discharge patients as soon as is safe.

Dr Ian Maidment, Senior Lecturer in Clinical Pharmacy at Aston University said: “This work adds to the evidence that anticholinergics should be avoided in a wide-range of populations, when possible. Regular medication review by a nurse, doctor or pharmacist may be a way of ensuring that medicines with anti-cholinergic effects are used appropriately.”